Over 200,000 US Veterans are suffering from Alzheimer's disease (AD) and this ?gure is expected to increase dramatically in the next few decades due to a higher prevalence of traumatic brain injury (TBI) and post- traumatic stress disorder (PTSD) that are risk factors of AD among soldiers returning from Iraq and Afghanistan wars. The apolipoprotein E (APOE) ?4 allele is the most prevalent genetic risk factor for AD, representing 60% of AD subjects in the general population. The apoE protein is a functional component of plasma involved in the transport of docosahexaenoic acid (DHA) into the brain which plays a key role in neurotransmission, membrane repair and cell signaling. Recent investigations have identi?ed loss of DHA within phosphatidylcholine (PC) in both the brain and blood of AD patients. Our previous work shows that pattern of DHA alterations seen in ?4 carriers with preclinical AD is similar to those seen in ?4 carriers with TBI or TBI +PTSD. While the brain is able to synthesize most lipids, DHA has to be acquired from the periphery since its de novo synthesis is insuf?cient to meet the high demand in the brain. Studies show that among ?4 carriers, transport of DHA to the brain is reduced compared to non-?4 carriers, contributing to the pro-in?ammatory and pro-amyloidogenic brain environment that is conducive to the development of AD. As such, increasing DHA transport into the brain could be important for preventing or treating AD among ?4 carriers who are at an exceptionally higher risk for developing AD and don't respond well to experimental AD treatments. Lyso-PC (LPC)-DHA is specially transported to the brain through a specialized transporter major facilitator superfamily domain containing 2A (mfsd2a) within the blood-brain-barrier (BBB). We have observed that the expression of mfds2a is reduced in the cerebrovasculature of ?4 carriers compared to non-?4 carriers, in humans and in a mouse model of AD with human APOE4 gene (E4FAD). We observed that LPC-DHA levels are reduced in the brain parenchyma of ?4 AD patients compared to ?4 controls and non-?4 AD patients and in E4FAD compared to E3FAD mice. We also observed an increase in matrix metalloproteinase 9 (MMP9) expression in ?4 AD patients and in E4FAD mice. We hypothesize that MMP9 activity is elevated in the presence of ?4 which leads to alterations of the cerebrovasculature, including reduced mfsd2a levels. This results in insuf?cient brain entry of LPC-DHA, in?ammation, and exacerbated AD pathology. To address this problem, we will characterize DHA containing PC and LPC species within the brains of AD and control subjects strati?ed by different APOE genotypes and quantify corresponding changes in mfsd2a expression. Using EFAD mice, we will generate temporal pro?les of PC and LPC-DHA changes and corresponding mfsd2a reduction and its relationship with AD pathology. Moreover, we will use both in vitro and in vivo approaches to determine whether the presence of the apoE4 isoform in the absence of mfsd2a leads to a reduction of LPC-DHA and free DHA transport into the brain and if boosting mfsd2a expression counteracts these effects. We will delve deeper into the fundamental role of MMP9 in the transport of lipids into the brain and evaluate the impact of MMP9-directed therapies on mfsd2a expression and LPC-DHA brain entry in AD.To this point, we have preliminary data indicating that increasing mfsd2a in the brain cerebrovasculature increases brain LPC-DHA levels and reduces in?ammation in older E4FAD mice with well-established AD pathology. We ?nd these observations to be extremely compelling as AD therapies have consistently failed in patients with 1) existing AD and 2) those carrying the ?4 allele. These preliminary ?ndings shows promise in treating both of these notoriously resistant populations. Overall, these studies will elucidate mechanisms by which MMP9-mediated loss of mfsd2a causes reduced uptake of DHA in the brain and, additionally, will explore therapeutic avenues to increase LPC-DHA transport into the brain to prevent and treat AD, particularly in ?4 carriers.